4 Connective Tissue

• Provides the structural integrity of tissues & organs ("glue" for stability)
• Provides mechanical properties – offering both tensile & compressive properties as needed
• Provides environment for differentiation & residence for immune cells (eg. plasma cells, macrophages)
• Facilitates exchange of metabolites, electrolytes & water
• Energy storage (eg. white adipose tissue)
• Heat production (eg. brown adipose tissue)1
• Repair & restoration of tissue architecture following damage (eg. nerve regeneration)

• one of the four basic tissue types that functions to support other tissues; made up of cells & the matrix
• it consists of several cell types & extracellular products which, together, provide essential functions of mechanical reinforcement, immune surveillance, transport/diffusion of nutrients and wastes, & energy storage (fat)
• Embryonically, connective tissue is derived from mesoderm/mesenchyme

Indigenous cells & Immigrant cells

• connective tissue cells that originate in the connective tissue itself
• Mesenchymal Cells
• Fibroblasts
• Adipocytes
• Osteogenic Cells (+ derivatives)
• Chondrogenic Cells (+ derivatives)

• multipotent stem cells that can differentiate into: myocytes (muscle cells), adipocytes (fat cells), chondrocytes (cartilage cells), osteoblasts (bone building cells), & neurons
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• mostly looking at cells’ nuclei & cytoplasm extends off into long processes
• typically reside in a very hydrated extracellular matrix

• most common cell in most CTs, both regular & irregular dense CT
• synthesize most ECM components (collagen, elastin, proteoglycans, glycoproteins)
• cytoplasm & ECM stain similarly - you usually just see nuclei
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• they have an elongated appearance with flattened, surf-board-like nuclei and cytoplasm with lots of RER & golgi
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• they have the capacity to differentiate into myofibroblasts (under both normal & wound-healing conditions)

• indigenous cell of CT that comes in two major varieties:
• white adipose tissue - lipid storage, unilocar
• brown adipose tissue - heat production, multilocar
• both derived from mesenchymal cells

• unilocular, meaning there’s one large lipid droplet per cell that’s so large it pushes the nucleus out to the periphery
• all you can really see for cytoplasm is a faint thin pink rim - most of the cell consists of a large lipid droplet
• between cells is a small amount of loose connective tissue with blood vessels (gives a “chicken-wire’ appearance)
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• multilocular because there are lots of lipid droplets in each cell
• used for heat production so there’s a rich blood supply that can help to convey the heat that’s produced to the rest of the body
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• called brown because cells have numerous mitochondria (containing colored cytochromes) + LOTS of blood vessels between cells

connective tissue cells that originate from hematopoietic stem cells in bone marrow, circulate in the blood, then move into connective tissue where they differentiate & subsequently function

• 1. Macrophages (derived from monocytes)
• 2. Mast cells
• 3. Lymphocytes
• 4. Plasma Cells (derived from B- Lymphocytes)

• large cells derived from blood monocytes that have migrated into CTs that phagocytose cellular debris, foreign bodies, & air-born particles
• have many roles in addition to scavenging debris, including important functions in both the innate & adaptive immune systems + infammation
• distinguishing characteristics: large size & their nuclei, which are large & irregularly shaped
• their cytoplasm is full of vacuoles (phagosomes) that contain phagocytosed material
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• type of immigrant cell of the CT that are critical for allergic reactions
• are derived from bone marrow
• have a spherical central nucleus surrounded by a cytoplasm PACKED with basophilic granules (polyanions, negatively charged molecules)
• exhibit metachromasia
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• degranulation of mast cell granules & release of histamine/heparin can lead to anaphylaxis (+ drop in BP, bronchoconstriction, rash)
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• are present in CTs but are called recirculating cells because they can move between blood & CTs
• typically they’re ubiquitous - aren’t many places where they can’t be found
• hallmark: small, dark nucleus surrounded only by a little cytoplasm
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• “if you see a cell nucleus that really doesn’t fit with the nuclei around it, consider it to be a wandering lymphocyte”

• residents of CTs, will never see them in the blood (B cells can be found in blood, but terminally differentiated they’re only in CT)
• are specialized for antibody (Ig) production
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• characteristic appearance: oval-shaped, with the nucleus on one side & an "apron” of eiosinophilic cytoplasm on the other

• heterochromatin in nucleus have distinctive “wagon wheel”/“clock-face” appearance
• contain lots of RER (synthesizing Igs) in cytoplasm, so they stain basophilically
• clear area between eiosinophilic cytoplasm & nucleus is the Golgi (where glycosylation + further processing of the IgGs occurs)
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B-lymphocytes that have left the circulation and move to the connective tissue; in the CT they differentiate and initiate the synthesis of immunoglobulins

• comprised of fibrils
• collagen alpha chains have glycines @ every 3rd residue
• 3 chains form a triple helix
• cross-linking between triple helices is what maintains collagen’s structural integrity - occurs between hydroxylysine & hydroxyproline
• this cross-linking is catalyzed by lysyl- & prolyl-hydroxylase, which REQUIRE co-factor ascorbic acid (vitamin C)
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• I – nearly everywhere; most abundant protein in the body
• II – cartilage mostly, especially articular
• III – many organs, forms reticular fibers

• Type I Collagen
• keloids can result from localized collagen accumulation (excess scar production)

• abundant in hyaline cartilage (found in all synovial joints)
• found in many organs during development
• in an adult, it can be found in the vitreous humor of the eye & the inner ear

• highly branched (unlike the other 2 kinds of collagen)
• visualization requires special silver stain
• located in many lymphoid organs, the liver, & reticular dermis (skin)
• reticular in latin means “little net” - type III collagen can have filtration functions

• filled with reticular fibers, aka branched type III collagen
• it supports channels in liver, lymph nodes, & spleen
• is also present in other organs for support (eg. dermis)
• again, requires a special silver stain to visualize
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• LOTS of branching (twigs on a tree)
• liverliverliverliver

• includes Type IV, which is one of the main components of the basement membrane
• many non-fibrillar collagens are associated with fibrils
• these represent most known collagens (28 & counting)
• generally aren’t too abundant; need special stains to visualize (eg. immunohistochemistry where you have an Ig specific to a component of the collagen)

• made up of elastin + microfibrils
• to synthesize, you start with a core of fibrilin, a glycoprotein that forms the “scaffold”
• can deposit tropoelastin on the fibrilin
• once tropoelastin is cross-linked, it becomes elastin
• the same enzyme that cross-links collagen (lysyl oxidase) also cross-links elastin (don’t forget vit C cofactor)

• caused by a mutation in fibrillin-1, meaning there is no effective “scaffold” to deposit tropoelastin on
• elastin molecules don’t work very well, which can lead to aneurisms, scoliosis, & hyperextensible joints
• in addition to acting as a scaffolf, fibrilin-1 also sequesters TGF-β & regulates its bioavailability
• excess TGF-β in Marfans may predispose to many of the phenotypes

• caused by mutations in elastin protein that leads to loose, wrinkled skin that lacks elasticity
• in severe cases, internal organs may be affected

• Water
• Proteoglycans
• Glycosaminoglycans (GAGs)
• Glycoproteins
• it's the background material within which all other connective tissue elements are embedded
• consists mainly of water that provides a route for communication + transport (by diffusion) between tissues
• a complex of GAGs, proteoglycans, & glycoproteins stabilizes the water

• is highly charged – has to do with an abundance of sulfate groups -thus hygroscopic (hydrated)
• this charge confers compressive resistance (eg. articular cartilage - lots of negative charges repel each other & therefore resist compression)
• there is very little protein in the ground substance which is why it stains poorly - often looks like an empty space
• permits nutrient/gas exchange (especially in
• avascular tissues like hyaline cartilage)

• linear polymers of repeating disaccharides [GAGs] covalently linked to a protein core
• are hydrophilic, negatively charged due to SULFATE groups on the sugar residues
• they account for the porous nature of CT that allows diffusion of metabolites & waste products to traverse to & from blood vessels

• Dense Regular
• Dense Irregular
• Loose (Areolar)
• Elastic
• Adipose
• Reticular
• Cartilage
• Bone

• see this in tendons (connecting muscle to bone) & ligaments (connecting bone to bone) where it provides tensile strength
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• red staining = densely packed type I collagen fibers arranged in parallel; fibroblasts are present wherever they can fit & are arranged in the same direction as the collagen

• composed of densely packed collagen fibers arranged irregularly through the tissue
• they still impart strength to the tissues in which they are found (eg. skin dermis)
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• a loose arrangement of fibers & cells surrounded by an abundance of ground substance
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• hallmark: lots & lots of “space” which is ground substance
• holds organs in place & attaches epithelial tissues to itself + other underlying tissues
• surrounds blood vessels & nerves

• Loose connective tissues contain FEWER extracellular fibrils, but are RICHER in cells (including fibroblasts)
• if CT is Loose, it’s automatically going to be irregular

• connective tissue that has a lot of elastic fibers
• can exist in 2 different forms:
• in blood vessels (elastic artery wall), you have sheets (lamellae) of elastic fibers
• can find branches elastic fibers in many other regions of the body (eg. dermis, skin is very elastic)
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• typically elastin stain is needed to visualize